ADENOCARCINOMA OF THE PANCREAS

Transcription

1 ADENOCARCINOMA OF THE PANCREAS Effective Date: November 2017

2 Copyright (2017) Alberta Health Services This material is protected by Canadian and other international copyright laws. All rights reserved. This material may not be copied, published, distributed or reproduced in any way in whole or in part without the express written permission of Alberta Health Services (please contact the Guideline Resource Unit Manager at CancerControl Alberta at material is intended for general information only and is provided on an "as is", "where is" basis. Although reasonable efforts were made to confirm the accuracy of the information, Alberta Health Services does not make any representation or warranty, express, implied or statutory, as to the accuracy, reliability, completeness, applicability or fitness for a particular purpose of such information. This material is not a substitute for the advice of a qualified health professional. Alberta Health Services expressly disclaims all liability for the use of these materials, and for any claims, actions, demands or suits arising from such use. The recommendations contained in this guideline are a consensus of the Alberta Provincial GI Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care. All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List. Participation of members of the Alberta Provincial GI Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial GI Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner. Page 2 of 11

3 BACKGROUND Adenocarcinoma of the pancreas is associated with a poor prognosis. Even after resection of small tumours without regional lymph node involvement, five-year survival rates remain low at around 20 percent. 1 The diagnosis of pancreas cancer may be preceded by non-specific symptoms (e.g.: fatigue, anorexia, weight loss, dull epigatric pain). Early satiety, malabsorption, steatorrhea, glucose intolerance, and jaundice (from extra-hepatic biliary obstruction) may also occur. Risk factors include age, male gender, chronic pancreatitis, diabetes mellitus type 2, germline mutations in P 16 and BRCA2, and a familial predisposition (e.g.: multiple endocrine neoplasia type 1, hereditary nonpolyposis colon cancer). There is a dose-response relationship with smoking 2 and an association with processed meat consumption. Although disease confined to the pancreas may be amenable to a pancreaticoduodenectomy or distal pancreatectomy, involvement of the celiac axis or superior mesenteric artery, venous occlusion at the confluence of the superior mesenteric and portal veins, or metastatic disease represents unequivocally unresectable disease. Direct extension to the duodenum, bile duct, or peri-pancreatic tissue with or without isolated involvement of the superior mesenteric vein or portal vein may still be amenable to resection. This guideline was developed to outline the management recommendations for patients with pancreatic cancer (adenocarcinoma). For specific recommendations for the management of malignant biliary obstruction, please refer to the Malignant Biliary Obstruction clinical practice guideline. GUIDELINE QUESTIONS What are the recommendations for the diagnostic workup of adult patients with adenocarcinoma of the pancreas? What are the treatment recommendations for adult patients with potentially curable adenocarcinoma of the pancreas? What are the management recommendations for adult patients with unresectable cancer of the pancreas? DEVELOPMENT AND REVISION HISTORY This guideline was reviewed and endorsed by the Alberta Provincial Gastrointestinal Tumour Team. Members of the Alberta Provincial Gastrointestinal Tumour Team include medical oncologists, radiation oncologists, surgical oncologists, hepatologists, gastroenterologists, interventional radiologists, nurses, nurse practitioners, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Gastrointestinal Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in January This guideline was revised in March 2009, August 2009, March 2010, June 2011, October 2013, March 2014, June 2015 and November Page 3 of 11

4 SEARCH STRATEGY This guideline was developed to promote evidence-based practice in Alberta. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team s interpretation of the data. For the 2017 update of this guideline, recommendations were modified based on a consensus discussion at the 2017 Annual Gastrointestinal Tumour Team Meeting. However, no formal update of the literature was performed. TARGET POPULATION The recommendations outlined in this guideline apply to adults over the age of 18 years with pancreatic cancer. Different principles may apply to pediatric patients. RECOMMENDATIONS AND DISCUSSION Suggested Diagnostic Work-Up A CT scan of the chest and abdomen with or without an MRI of the abdomen (and other tests, as clinically indicated) distinguish between resectable and unresectable disease. Page 4 of 11

5 Stage Information Table 1. AJCC Cancer Staging System for Adenocarcinoma of the Pancreas and Ampulla, Seventh Edition. Stage Tumour Stage Regional Lymph Node Involvement Metastases Stage 0 Tis Carcinoma in situ N0 None M0 Absent Stage IA T1 Tumour 2 cm in size and confined to pancreas N0 None M0 Absent Stage IB T2 Tumour > 2 cm and confined to pancreas N0 None M0 Absent Stage IIA T3 Extension beyond confines of pancreas but without N0 None M0 Absent involvement of either celiac axis or superior mesenteric artery Stage IIB T1-3 As described above N1 Present M0 Absent Stage III T4 Involvement of celiac axis or superior mesenteric artery Nany As above M0 Absent Stage IV Tany As described above Nany As above M1 Present Goals and Recommendations for Potentially Curable Adenocarcinoma of the Pancreas 1. To render the patient free of disease and to delay or prevent recurrence. 2. To improve the patient s quality of life. Table 2. Treatment Recommendations for Potentially Curable Adenocarcinoma of the Pancreas. Stage Recommendations Stage 0 TisN0M0 Perform Whipple pancreaticoduodenectomy or distal pancreatectomy to resect disease with macroscopically clear margins. Resectable Disease Perform Whipple pancreaticoduodenectomy or distal pancreatectomy to resect disease with Stage IA T1N0M0 macroscopically clear margins. Stage IB T2N0M0 Consider adjuvant treatment on a clinical trial, if available. Stage IIA T3N0M0 Six four-week cycles of IV Gemcitabine with oral Capecitabine 3. Stage IIB T1-3N1M0 Alternatively, six four-week cycles of Leucovorin 20 mg/m 2 IV followed by 5-Fluorouracil 425 mg/m 2 IV on each of five consecutive days has been shown to increase the median survival from 15.5 months to 20.1 months, the two-year survival from 30% to 40%, and the five-year survival from 8% to 21% when compared to no further treatment. 4-6 Alternatively, six four-week cycles of Gemcitabine (1,000 mg/m 2 IV over thirty minutes on days 1,8 and 15) 5,7 may be offered. Adjuvant chemotherapy should be initiated within twelve weeks of surgery. Follow-up after resection: There is no evidence of survival improvement with close follow-up based on literature However, routine surveillance enables detection of asymptomatic recurrences. Systemic/palliative treatment has advanced over the last years but only patient with sufficient performance status is eligible; therefore, routine surveillance may improve the likelihood of detecting recurrence at a point when patients are well enough to receive chemotherapy. Goals and Recommendations for Unresectable Adenocarcinoma of the Pancreas 1. Maintain or improve the patient s quality of life (control or delay onset of tumour-related symptoms). 2. To prolong life, if possible. 3. Relieve biliary obstruction, if possible, by a. Endoscopic retrograde cholangiopancreatography with stent placement, b. Percutaneous transhepatic cholangiography with stent placement, or c. Palliative surgery. 4. Relieve pain with analgesics, celiac ganglion ablation (either percutaneous or endoscopic splanchniccectomy), or radiation. 5. Consider treatment on a clinical trial, if available. 6. To provide early access to palliative care services when appropriate. Page 5 of 11

6 Table 3. Management Recommendations for Unresectable Adenocarcinoma of the Pancreas. Stage Locally Advanced Stage III T4NanyM0 Metastatic Disease Stage IV TanyNanyM1 Recommendations First line treatment A discussion addressing patient preferences concerning the balance of toxicity and efficacy should guide the decision for first line therapy for patients with good performance status. FOLFIRINOX For carefully selected patients with metastatic disease, performance status (ECOG 0 or 1), age 75 years, and a normal or nearly normal bilirubin, FOLFIRINOX prolongs overall survival (11.1 months versus 6.8 months, HR 0.57, 95% CI , p = ) and delays the deterioration in quality of life when compared to Gemcitabine alone. 11,12 The rate of grade 3/4 toxicities emphasizes the need for education, monitoring, and active management (see Table 4 and 5 below). It should only be administered in the Tertiary or Regional Cancer Centres. The Provincial Gastrointestinal Tumour Team agree that FOLFIRINOX may also be considered for patients with locally advanced disease given that a high response rate may result in the conversion of some patients to resectable disease. At present, no randomized studies have explored the use of FOLFIRINOX in locally advanced pancreatic cancer patients (see Appendix A for a list of current clinical trials using this regimen). Several retrospective reviews have demonstrated the efficacy and tolerability of FOLFIRINOX in this patient group, despite the use of dose modifications and adverse events nab-paclitaxel plus Gemcitabine Patients may also be considered for treatment with nab-paclitaxel plus Gemcitabine. An international, phase III trial of 861 metastatic pancreatic cancer patients compared the efficacy and safety of nab-paclitaxel plus Gemcitabine versus Gemcitabine alone. 16 Median overall survival was 8.5 months in the intervention arm compared to 6.7 months in the control arm (HR 0.72, 95% CI , p<0.001). Median progression-free survival was 5.5 months versus 3.7 months in the nab-paclitaxel plus Gemcitabine versus Gemcitabine alone group, respectively (HR 0.69, 95% CI , p<0.001). According to independent review, the response rate was 23% versus 7% in the nab-paclitaxel plus Gemcitabine group versus the control group, respectively (p<0.001). The Provincial Gastrointestinal Tumour Team adapts the eligibility criteria based on the above mentioned phase III study. 16 The Provincial Gastrointestinal Tumour Team agree that nab-paclitaxel plus Gemcitabine may also be considered for patients with locally advanced disease. Patients eligible for nab-paclitaxel plus Gemcitabine should meet the following criteria: 18 years of age Karnofsky performance status score 70 Have not previously received chemotherapy for metastatic disease (patient could have received treatment with Fluorouracil or Gemcitabine as a radiation sensitizer in the adjuvant setting if the treatment had been received at least 6 months ago) Have histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of the pancreas Have adequate hematologic, hepatic, and renal function, including: o Absolute neutrophil count of 1.5x10 9 per litre o Hemoglobin level of 9 g per deciliter o Bilirubin level at or below the upper limit of the normal range Gemcitabine For patients with a performance status of ECOG 2, Gemcitabine (1,000 mg/m 2 IV over thirty minutes once weekly for seven of eight weeks and subsequently weekly for three of four weeks) has been shown to offer a clinical benefit response (improvement in pain, performance status, and weight) in 23.8%. 17,18 In addition, it may prolong median survival (to 5.65 months) and improve twelve-month survival (to 18%). Treatment should be continued until progression or until significant clinical deterioration secondary to tumour-related symptoms. Page 6 of 11

7 Stage Recommendations Second line treatment After progression on Gemcitabine, treatment with Leucovorin (200 mg/m 2 IV over thirty minutes) followed by a continuous intravenous infusion of 5-Fluorouracil (2,000 mg/m 2 over twenty-four hours) on days 1, 8, 15, and 22 with Oxaliplatin (85 mg/m 2 IV over two hours) on days 8 and 22 of every six week cycle ( OFF regimen) has been shown to increase median overall survival compared to Leucovorin and 5-Fluorouracil alone; from 3.3 months to 5.9 months (p =0.010) in patients with a good performance status. 19 Note that FOLFOX is not interchangeable with OFF as it has been shown to be inferior to Leucovorin and 5-Fluorouracil in terms of OS in the second line 20. Nanoliposomal irinotecan (80 mg/m², equivalent to 70 mg/m² of irinotecan base)with 5- Fluorouracil and Leucovorin is an acceptable second line treatment option and may be considered for use after Health Canada approval is obtained as the addition of nanoliposomal irinotecan increased median overall survival to 6.1m (95%CI ) compared to 4.2m (95%CI m) in the fluorouracil and folinic acid alone group (HR 0.67, 95% CI ; p=0.012). 12 FOLFIRINOX Regimen: 11 Oxaliplatin 85 mg/m 2 IV over two hours Leucovorin 400 mg/m 2 IV over two hours Irinotecan 180 mg/m 2 IV over ninety minutes 5-Fluorouracil 400 mg/m 2 IV bolus 5-Fluorouracil 2,400 mg/m 2 CIV over forty-six hours Table 4. Reported Adverse Events with FOLFIRINOX or Gemcitabine Adverse Events (Grade 3/4 Toxicities) FOLFIRINOX Gemcitabine Statistics Neutropenia Grade 3: Neutrophils % 21.0% p < Grade 4: Neutrophils <0.5 Febrile Neutropenia 5.4% 1.2% p = 0.03 Thrombocytopenia Grade 3: Platelets % 3.6% p = 0.04 Grade 4: Platelets <25 Fatigue Grade 3: Difficulty performing some ADLs 23.6% 17.8% NS Grade 4: Interfering with ADLs Emesis Grade 3: 6 episodes, 24h IV hydration 14.5% 8.3% NS Grade 4: Life-threatening consequences Diarrhea Grade 3: 7 stools/d, 24h IV fluids, hospitalization 12.7% 1.8% p < Grade 4: Life-threatening consequences Peripheral Neuropathy 9.0% 0.0% p < Page 7 of 11

8 Table 5. FOLFIRINOX Dose Modification Recommendations. Toxicity Decision at Day 0 Proceed Delay Occurrence Irinotecan Dose Oxaliplatin Dose 5- Fluorouracil Bolus Dose 5- Fluorouracil CIV Dose Neutrophils /L < /L First 150 mg/m 2 85 mg/m 2 Omit 2,400 mg/m 2 or mid-cycle febrile neutropenia* Second 150 mg/m 2 60 mg/m 2 Omit 2,400 mg/m 2 Platelets /L < /L First 180 mg/m 2 60 mg/m mg/m 2 1,800 mg/m 2 or mid-cycle platelet count < /L* Second 150 mg/m 2 60 mg/m mg/m 2 1,800 mg/m 2 Diarrhea Grade 3/4 First 150 mg/m 2 85 mg/m 2 Omit 2,400 mg/m 2 Grade 3/4 Second 150 mg/m 2 60 mg/m 2 Omit 1,800 mg/m 2 Mucositis Grade 3/4 First 180 mg/m 2 85 mg/m mg/m 2 1,800 mg/m 2 Hand-foot syndrome Grade 3/4 First 180 mg/m 2 85 mg/m mg/m 2 1,800 mg/m 2 * Discontinue treatment after third occurrence or if toxicity fails to resolve after two-week delay. GLOSSARY OF ABBREVIATIONS Acronym ADL AJCC CI CT ECOG FOLFIRINOX HR IV MRI OFF TNM Description activities of daily living American Joint Committee on Cancer confidence interval computed tomography Eastern Cooperative Oncology Group 5-fluorouracil + leucovorin + oxaliplatin + irinotecan hazard ratio intravenous magnetic resonance imaging 5-fluorouracil + leucovorin + oxaliplatin tumour-node-metastasis DISSEMINATION Present the guideline at the local and provincial tumour team meetings and weekly rounds. Post the guideline on the Alberta Health Services website. Send an electronic notification of the new guideline to all members of CancerControl Alberta. MAINTENANCE A formal review of the guideline will be conducted at the Annual Provincial Meeting in If critical new evidence is brought forward before that time, the guideline working group members will revise and update the document accordingly. Page 8 of 11

9 REFERENCES 1. Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg 1995 discussion 731-3; Jun;221(6): Level of Evidence: 2b 2. Nothlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN. Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. J Natl Cancer Inst 2005 Oct 5;97(19): Level of Evidence: 2c 3. Neoptolemos JP, Palmer D, Ghaneh P, Valle JW, Cunningham D, Wadsley J, et al. ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma. J Clin Oncol ASCO Annual Meeting;34(suppl; abstr LBA4006). 4. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004 Mar 18;350(12): Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010 Sep 8;304(10): Neoptolemos JP, Stocken DD, Tudur Smith C, Bassi C, Ghaneh P, Owen E, et al. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J Cancer 2009 Jan 27;100(2): Level of Evidence: 1a 7. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007 Jan 17;297(3): Nilsson LN, Keane MG, Shamali A, Millastre Bocos J, Marijinissen van Zanten M, Antila A, et al. Nature and management of pancreatic mucinous cystic neoplasm (MCN): A systematic review of the literature. Pancreatology 2016 Nov - Dec;16(6): Level of Evidence: 2a 9. Witkowski ER, Smith JK, Ragulin-Coyne E, Ng SC, Shah SA, Tseng JF. Is it worth looking? Abdominal imaging after pancreatic cancer resection: a national study. J Gastrointest Surg 2012 Jan;16(1): Level of Evidence: 2c 10. Tzeng CW, Fleming JB, Lee JE, Wang X, Pisters PW, Vauthey JN, et al. Yield of clinical and radiographic surveillance in patients with resected pancreatic adenocarcinoma following multimodal therapy. HPB (Oxford) 2012 Jun;14(6): Level of Evidence: 2b 11. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011 May 12;364(19): Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016 Feb 6;387(10018): Page 9 of 11

10 13. Gunturu KS, Yao X, Cong X, Thumar JR, Hochster HS, Stein SM, et al. FOLFIRINOX for locally advanced and metastatic pancreatic cancer: single institution retrospective review of efficacy and toxicity. Med Oncol 2013 Mar;30(1): Epub 2012 Dec 28. Level of Evidence: Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, et al. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer 2012 May 29;12: Level of Evidence: Peddi PF, Lubner S, McWilliams R, Tan BR, Picus J, Sorscher SM, et al. Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma. JOP 2012 Sep 10;13(5): Level of Evidence: Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013 Oct 31;369(18): Burris HA,3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997 Jun;15(6): Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007 May 20;25(15): Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014 Aug 10;32(23): Gill S, Ko YJ, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, et al. PANCREOX: A Randomized Phase III Study of 5-Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol 2016 Sep 12. Page 10 of 11

11 APPENDIX A The following is a list of current clinical trials using FOLFIRINOX in locally advanced pancreatic cancer patients (obtained from on March 10, 2015): Immunotherapy Study in Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer (NCT ) FOLFIRINOX for Unresectable Locally Advanced and Borderline Resectable Pancreatic Cancer (NCT ) ACTIVE BUT NOT RECRUITING FOLFIRINOX Plus PF in Patients With Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma (NCT ) ACTIVE BUT NOT RECRUITING Study of Modified FOLFIRINOX in Advanced Pancreatic Cancer (NCT ) ACTIVE BUT NOT RECRUITING A Phase II Study of sig12d LODER in Combination With Chemotherapy in Patients With Unresectable Locally Advanced Pancreatic Cancer (NCT ) Proton w/folfirinox-losartan for Pancreatic Cancer (NCT ) Pancreatic Carcinoma: Chemoradiation Compared With Chemotherapy Alone After Induction Chemotherapy (NCT ) Phase III FOLFIRINOX (mffx) +/- SBRT in Locally Advanced Pancreatic Cancer (NCT ) Chemotherapy for Patients With Locally Advanced Pancreatic Cancer (LAPC) With Additional Chemo-radiotherapy (CRT) for Patients With Borderline Resectable Tumours (NCT ) A Phase II Study of Locally Advanced Pancreatic Cancer (NCT )- ENROLLING BY INVITIATION Efficacy and Feasibility of Combining FOLFIRINOX and Stereotactic Radiotherapy for Patients with Irresectable Locally Advanced Pancreatic Cancer. (NCT ) Induction Chemotherapy, FOLFIRINOX Followed With Concurrent Capecitabine and Radiation Therapy in Inoperable Locally Advanced Cancer of the Pancreas (NCT ) Trial to Investigate Intensified Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Cancer (NCT ) LDE225 With Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan for Untreated Advanced Pancreatic Cancer (NCT ) Effects of Folfirinox and Stereotactic Body Radiation Therapy for Advanced Pancreatic Cancer (NCT ) Page 11 of 11